This is a new application for a R21. The long-term objective of this grant is to use phage display libraries to identify tissue specific homing peptids for the trabecular meshwork (TM) that can be used as therapeutic delivery agents to control and lower intraocular pressure. The glaucomas, which lead to irreversible loss of retinal ganglion cells, affect approximately 67 million people worldwide. They are commonly associated with elevated levels of intraocular pressure (IOP) due to a reduction in aqueous humor outflow from the TM. Although reduced drainage of aqueous humor through the TM accounts for at least 90% of abnormalities resulting in glaucoma, there are very few drugs that can specifically target the TM with the goal of increasing aqueous humor outflow. One way to target drug deliver is to use homing peptides attached to the compound or cloned into the viral coat. These homing peptides are then used to generate tissue specific delivery systems in vivo and reduce targeting of unwanted tissue interactions. To identify homing peptides for the TM, we plan to use the Cx7C phage library previously shown to produce in vivo tissue specific homing peptides. We also plan to generate a phage display library that is biased towards the a4b1 integrin sequence motif, PRARI. Published studies from our laboratory have shown that this PRARI peptide can be used to target the TM. In past studies, this peptide caused an increase in outflow facility in cultured anterior segments. It is our goal to produce a more specific PRARI peptide with a higher affinity. The identification of homing peptides for the TM would have multiple uses for the treatment for glaucoma. In addition to targeted drug delivery and generation of tissue specific viral vectors, these peptides could be used as biomarkers for cell stem delivery and as imaging tools for glaucoma surgery.
Glaucoma is the second most common cause of blindness in the U.S. and the most common cause of blindness among African-Americans. Attempts to understand and treat the causes(s) of this disease have been hampered by the molecular heterogeneity of the disease and the lack of well-defined biomarkers to distinguish the causes. The goal of this project is to phage display to generate tissue specific peptides that could then be used to develop targeted treatments for glaucoma.
|Gagen, Debjani; Faralli, Jennifer A; Filla, Mark S et al. (2014) The role of integrins in the trabecular meshwork. J Ocul Pharmacol Ther 30:110-20|